Pasireotide: successful treatment of a sparsely granulated tumour in a resistant case of acromegaly.

The granulation pattern of somatotroph adenomas is well known to be associated with differing clinical and biochemical characteristics, and it has been shown that sparsely granulated tumours respond poorly to commonly used somatostatin receptor ligands (SRLs). We report a challenging case of acromegaly with a sparsely granulated tumour resistant to multiple modalities of treatment, ultimately achieving biochemical control with pasireotide. A 26-year-old lady presented with classical features of acromegaly, which was confirmed by an oral glucose tolerance test. Insulin-like growth factor 1 (IGF1) was 1710 µg/L (103-310 µg/L) and mean growth hormone (GH) was >600 U/L. MRI scan showed a 4 cm pituitary macroadenoma with suprasellar extension and right-sided cavernous sinus invasion. She underwent trans-sphenoidal pituitary surgery. Histology displayed moderate amounts of sparsely granular eosinophilic cytoplasm, staining only for GH. Postoperative investigations showed uncontrolled disease (IGF1:1474 µg/L, mean GH:228 U/L) and residual tumour in the cavernous sinus. She received external beam fractionated radiation. Over the years, she received octreotide LAR (up to 30 mg), lanreotide (up to 120 mg) two weekly, cabergoline, pegvisomant and stereotactic radiosurgery to no avail. Only pegvisomant resulted in an element of disease control; however, this had to be stopped due to abnormal liver function tests. Fifteen years after the diagnosis, she was started on pasireotide 40 mg monthly. Within a month, her IGF1 dropped and has remained within the normal range (103-310 µg/L). Pasireotide has been well tolerated, and there has been significant clinical improvement. Somatostatin receptor subtyping revealed a positivity score of two for both sst5 and sst2a subtypes. LEARNING POINTS: Age, size of the tumour, GH levels on presentation, histopathological type and the somatostatin receptor status of the tumour in acromegaly should be reviewed in patients who poorly respond to first-generation somatostatin receptor ligands.Tumours that respond poorly to first-generation somatostatin receptor ligands, especially sparsely granulated somatotroph adenomas, can respond to pasireotide and treatment should be considered early in the management of resistant tumours.Patients with membranous expression of sst5 are likely to be more responsive to pasireotide.

Effects of short-term sitagliptin treatment on immune parameters in healthy individuals, a randomized placebo-controlled study.

Sitagliptin, a dipeptidyl-peptidase 4 (DPP-4) inhibitor, improves blood glucose control in patients with type 2 diabetes by blocking cleavage of glucagon-like peptide 1 (GLP-1). In type 2 diabetes patients sitagliptin use is associated with an increase in minor infections, and in new-onset type 1 diabetes patients the ability of sitagliptin to dampen autoimmunity is currently being tested. DPP-4, also known as CD26, is expressed on leucocytes and can inactivate many chemokines important for leucocyte migration, as well as act as a co-stimulatory molecule on T cells. Therefore, this study was conducted to test whether sitagliptin is immunomodulatory. In this randomized, placebo-controlled trial, healthy volunteers were given sitagliptin or placebo daily for 28 days, and blood was drawn for immune assays. No significant differences were observed in the percentage of leucocyte subsets within peripheral blood mononuclear cells (PBMCs), plasma chemokine/cytokine levels or cytokines released by stimulation of PBMCs with either lipopolysaccharide (LPS) or anti-CD3. Individuals taking sitagliptin displayed increases in the percentage of cells expressing higher levels of CD26 at early time-points compared to placebo controls, but these differences resolved by day 28 of treatment. Therefore, in healthy volunteers, treatment with sitagliptin daily for 28 days does not overtly alter systemic immune function.

A randomised controlled trial of the effect of continuous electronic physiological monitoring on the adverse event rate in high risk medical and surgical patients.

We conducted a randomised controlled trial of mandated five-channel physiological monitoring vs standard care, in acute medical and surgical wards in a single UK teaching hospital. In all, 402 high-risk medical and surgical patients were studied. The primary outcome was the proportion of patients experiencing one or more major adverse events, including urgent staff calls, changes to higher care levels, cardiac arrests or death, in 96 h following randomisation. Secondary outcomes were the proportion of patients requiring acute treatment changes, and the 30-day and hospital mortality. In the 96 h following randomisation, 113 (56%) patients in the monitored arm and 116 (58%) in the control arm (OR 0.94, 95% CI 0.63-1.40, p = 0.76) had a major event. An acute change in treatment was necessary in 107 (53%) monitored patients and 101 (50%) control patients (OR 0.55, 95% CI 0.87-1.29). Thirty-four (17%) monitored patients and 35 (17%) control patients died within 30 days. Thirteen patients in the control group received full five-channel monitoring at the request of the ward staff. We conclude that mandated electronic vital signs monitoring in high risk medical and surgical patients has no effect on adverse events or mortality.

Deep wound infection after proximal femoral fracture: consequences and costs.

The purpose of this study was to assess the impact of deep wound infection after surgery for proximal femoral fracture (PFF) on the patient in terms of mortality and social consequences, and on the National Health Service in terms of financial burden. Sixty-one cases of PFF over a six-year period were complicated with deep surgical wound infection. These cases were compared with a matched control group of 122 patients without infection. Infected cases had greatly increased hospital stay (P<0.001), were 4.5 times less likely to survive to discharge (P=0.002), and if they survived, were three times less likely to return to their original residence (P=0.05). The total cost of treatment per infected case was 24,410 pound sterling compared with 7210 pound sterling for controls (P<0.001). Meticillin-resistant Staphylococcus aureus (MRSA) infection increased admission length and cost compared with non-MRSA infection (P=0.02). Deep wound infection after PFF is a devastating and costly complication for both the patient and the healthcare services. The cost consequences should be considered when allocating resources to trauma services to ensure adequate provision to minimize infection risks and to accommodate treatment costs in this vulnerable group.

Perioperative fluid volume optimization following proximal femoral fracture.

BACKGROUND: Proximal Femoral Fracture (PFF) or 'hip fracture' is a frequent injury, and adverse outcomes are common. Several factors suggest the importance of developing techniques to optimize intravascular fluid volume. These may include protocols that enhance the efficacy of clinicians' assessments, invasive techniques such as oesophageal Doppler or central venous pressure monitoring, or advanced non-invasive techniques such as plethysmographic pulse volume determination. OBJECTIVES: To determine the optimal method of fluid volume optimization for adult patients undergoing surgical repair of PFF. Comparisons of fluid types, of blood transfusion strategies or of pharmacological interventions are not considered in this review. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library, issue 4, 2003), MEDLINE (1985 to 2003), EMBASE (1985 to 2003), and bibliographies of retrieved articles. Relevant journals and conference proceedings were handsearched. SELECTION CRITERIA: Randomized controlled studies comparing a fluid optimization intervention with normal practice or with another fluid optimization intervention, in patients following PFF undergoing surgery of any type under anaesthesia of any type. DATA COLLECTION AND ANALYSIS: Searches and exclusion of clearly irrelevant articles were performed by one reviewer. Two reviewers examined independently the remaining studies, extracting study quality and results data. A wide range of short- and long-term outcome data were sought. Studies were excluded if they did not meet selection criteria or if results were likely to be biased. Due to inconsistent data reporting, combination of data was not generally possible. MAIN RESULTS: Searches identified four trials, of which two studies, randomizing a total of 130 patients, were of adequate quality and addressed the review question. Both studies were of invasive advanced haemodynamic monitoring, either oesophageal Doppler ultrasonography or central venous pressure monitoring, during the intraoperative period only. In both, invasive monitoring led to significant increases in fluid volumes infused and reductions in length of hospital stay. The pooled Peto odds ratio for in-hospital fatality was 1.44 (95% confidence interval 0.45-4.62). Neither study followed patients beyond hospital discharge or assessed functional outcomes. No serious complications were directly attributable to the interventions. There were no studies of protocol-guided fluid optimization or of advanced non-invasive techniques. REVIEWER'S CONCLUSIONS: Invasive methods of fluid optimization during surgery may shorten hospital stay, but their effects on other important, patient-centred, longer-term outcomes are uncertain. Adverse effects on fatality cannot be excluded. Other fluid optimization techniques have not been evaluated. The lack of randomized studies of adequate quality addressing this important question is disappointing. More research is needed.

Time-frequency analysis of the ECG in the diagnosis of vasovagal syndrome in older people.

The Smoothed Pseudo Wigner-Ville Distribution (SPWVD) is used for the time-frequency analysis of variations in RR interval. A novel technique to determine the smoothing window lengths is implemented, and a new heart rate variability (HRV) metric is developed, instantaneous center frequency variability (ICFV), which uses the time-frequency map generated by the SPWVD. The technique is then applied to 50 patients with unexplained falls and age > 60, undergoing head-upright tilt table testing (HUT). Eighteen of the patients were diagnosed with vasovagal syndrome. Attempts at syncope prediction using the new metric is an improvement on traditional techniques: an ICFV less than 0.07 Hz from 90 s to 180 s after tilt is predictive of a negative test (negative predictive value: 0.77). The comorbidity and autonomic degeneration present in elderly patients are thought to be responsible for lowering the negative predictive value.

Subjective barriers to prevent wandering of cognitively impaired people.

BACKGROUND: People with dementia often wander, at times putting themselves at risk and presenting challenges to carers and institutional staff. Traditional interventions to prevent wandering include restraint, drugs and locked doors. Cognitively impaired people may respond to environmental stimuli (sounds, images, smells) in ways distinct from healthy people. This has led to trials of visual and other selective barriers (such as mirrors, camouflage, grids/stripes of tape) that may reduce wandering. OBJECTIVES: We assess the effect of subjective exit modifications on the wandering behaviour of cognitively impaired people. The second objective is to inform the direction and methods of future research. SEARCH STRATEGY: The search strategy includes electronic searches of relevant bibliographic and trials databases, citation indices and relevant medical journals. SELECTION CRITERIA: Randomized controlled trials and controlled trials provide the highest quality evidence, but interrupted time series are also considered as they may contribute useful information. Participants are people with dementia or cognitive impairment who wander, of any age, and in any care environment - hospital, other institution, or their own home. Interventions comprise exit modifications that aim to function as subjective barriers to prevent the wandering of cognitively impaired people. Locks, physical restraints, electronic tagging and other types of barrier are not included. DATA COLLECTION AND ANALYSIS: The criteria for inclusion or exclusion of studies are applied independently by two reviewers. All outcomes that are meaningful to people making decisions about the care of wanderers are recorded. These include the number of exits or carer interventions, resource use, acceptability of the intervention and the effects on carer and wanderer anxiety or distress. heterogeneity of clinical area, of study design and of intervention was substantial. MAIN RESULTS: No randomized controlled or controlled trials were found. The other experimental studies that we identified were unsatisfactory. Most were vulnerable to bias, particularly performance bias; most did not classify patients according to type or severity of dementia; in all studies, outcomes were measured only in terms of wandering frequency rather than more broadly in terms of quality of life, resource use, anxiety and distress; no studies included patients with delirium; no studies were based in patients' homes. REVIEWER'S CONCLUSIONS: There is no evidence that subjective barriers prevent wandering in cognitively impaired people.

CT appearance of the adrenal glands in adrenocorticotrophic hormone-dependent Cushing's syndrome.

OBJECTIVE: The purpose of this study was to describe the size and appearance of the adrenal glands on CT in patients with adrenocorticotrophic hormone (ACTH)-dependent Cushing's syndrome and to correlate gland dimensions with circulating cortisol and ACTH levels. MATERIALS AND METHODS: We retrospectively analyzed clinical, biochemical, and imaging data for 53 patients referred for CT of the adrenals as part of an investigation for ACTH-dependent Cushing's syndrome at our institution between 1988 and 1997. Two observers, who were unaware of the endocrine data, measured the body and limb widths of the adrenal glands using an electronic cursor. RESULTS: Of the 53 patients, 37 (70%) were shown to have enlarged adrenal glands on CT. The mean width of the adrenal limbs positively correlated with the circulating cortisol and ACTH levels. The adrenals were larger in patients with ectopic ACTH syndrome than in patients with Cushing's disease (p < .02). Ten patients (19%) had nodules that were 10 mm or greater in diameter. CONCLUSION: The adrenal glands were often enlarged in patients with ACTH-dependent Cushing's syndrome, and the enlargement could be quantified on CT. However, having normalsized adrenals (observed in 30% the patients in our study) did not preclude such a diagnosis. We found that adrenal limb width positively correlates with ACTH and cortisol levels.

A critical analysis of the value of simultaneous inferior petrosal sinus sampling in Cushing's disease and the occult ectopic adrenocorticotropin syndrome.

The clinical, biochemical, and radiological features of pituitary ACTH-dependent Cushing's syndrome (CS) [Cushing's disease (CD)] are often indistinguishable from those of occult ectopic ACTH-dependent CS (oEAS). We have evaluated, retrospectively, the results of simultaneous bilateral inferior petrosal sinus (IPS) ACTH sampling before and after CRH stimulation in 128 patients with ACTH-dependent CS: 107 patients with CD, 6 with oEAS, 1 with an adrenal adenoma, 1 with a pituitary gangliocytoma, and 1 with Nelson's syndrome; while, in the remaining 12, the source remains unclear. One hundred seven patients received human-sequence CRH (hCRH), and 11 received ovine CRH; another 6 patients underwent stimulation with desmopressin and hCRH, and 4 with desmopressin alone. A successful bilateral IPS catheterization and sampling (IPSCS) rate of 87.5% was obtained only after considerable experience had been gained. Sixty-nine patients with CD underwent successful bilateral IPSCS: the IPS-to-peripheral ratio of plasma ACTH value (IPS/P) rose from 9.5 +/- 1.4 to a maximum ratio of 55.8 +/- 7.5 in 67 patients, after CRH stimulation. The maximum ratio was obtained at 5 min in 60 of the 69 patients with CD; however, all 69 patients obtained a ratio of more than 2, at that time. In contrast, the 6 patients with occult ACTH-secreting neoplasms had a maximal IPS/P ratio of 1.3 +/- 0.16, and this did not change after CRH stimulation. A bilateral IPS/P ratio more than 2, obtained 5 min after CRH stimulation, had a sensitivity of 97% and a specificity of 100% in diagnosing CD. Two patients with proven active CD had an IPS/P ratio of less than 2. After successful bilateral IPSCS, the gradients between the IPS ACTH concentrations [IPS ACTH gradient (IPSG)] of more than 1.4, at 5 min after CRH stimulation, had a sensitivity of 83% in correctly lateralizing the pituitary microadenoma, compared with 72% sensitivity for magnetic resonance imaging (MRI) scanning. Furthermore, when IPSG and MRI findings were contradictory, IPSG was more often correct than MRI scanning. Although oEAS is a relatively uncommon cause of ACTH-dependent hypercortisolism (5.5% in our series), the accurate diagnosis of ACTH-dependent CS and localization of an intrapituitary microadenoma requires bilateral IPSCS with CRH stimulation, provided that the appropriate technical experience is available. hCRH is as effective a secretagogue as ovine CRH, and either may be used. The value of the combination of CRH and desmopressin stimulation requires more detailed investigation.

Menstrual abnormalities in women with Cushing's disease are correlated with hypercortisolemia rather than raised circulating androgen levels.

Menstrual irregularity is a common complaint at presentation in women with Cushing's syndrome, although the etiology has been little studied. We have assessed 45 female patients (median age, 32 yr; range, 16-41 yr) with newly diagnosed pituitary-dependent Cushing's syndrome. Patients were subdivided into 4 groups according to the duration of their menstrual cycle: normal cycles (NC; 26-30 days), oligomenorrhea (OL; 31-120 days), amenorrhea (AM; > 120 days), and polymenorrhea (PM; < 26 days). Blood was taken at 0900 h for measurement of LH, FSH, PRL, testosterone, androstenedione, dehydroepiandrosterone sulfate, estradiol (E2), sex hormone-binding globulin (SHBG), and ACTH; cortisol was sampled at 0900, 1800, and 2400 h. The LH and FSH responses to 100 micrograms GnRH were analyzed in 23 patients. Statistical analysis was performed using the nonparametric Mann-Whitney U and Spearman tests. Only 9 patients had NC (20%), 14 had OL (31.1%), 15 had AM (33.3%), and 4 had PM (8.8%), whereas 3 had variable cycles (6.7%). By group, AM patients had lower serum E2 levels (median, 110 pmol/L) than OL patients (225 pmol/L; P < 0.05) or NC patients (279 pmol/L; P < 0.05), and higher serum cortisol levels at 0900 h (800 vs. 602 and 580 nmol/L, respectively; P < 0.05) and 1800 h (816 vs. 557 and 523 nmol/L, respectively; P < 0.05) and higher mean values from 6 samples obtained through the day (753 vs. 491 and 459 nmol/L, respectively; P < 0.05). For the whole group of patients there was a negative correlation between serum E2 and cortisol at 0900 h (r = -0.50; P < 0.01) and 1800 h (r = -0.56; P < 0.01) and with mean cortisol (r = -0.46; P < 0.05). No significant correlation was found between any serum androgen and E2 or cortisol. The LH response to GnRH was normal in 43.5% of the patients, exaggerated in 52.1%, and decreased in 4.4%, but there were no significant differences among the menstrual groups. No differences were found in any other parameter. In summary, in our study 80% of patients with Cushing's syndrome had menstrual irregularity, and this was most closely related to serum cortisol rather than to circulating androgens. Patients with AM had higher levels of cortisol and lower levels of E2, while the GnRH response was either normal or exaggerated. Our data suggest that the menstrual irregularity in Cushing's disease appears to be the result of hypercortisolemic inhibition of gonadotropin release acting at a hypothalamic level, rather than raised circulating androgen levels.

Stereoselective pharmacokinetics of tocainide in human uraemic patients and in healthy subjects.

The disposition of tocainide enantiomers were examined in healthy human subjects and uraemic patients following a single i.v. dose (200 mg) of racemic tocainide hydrochloride. In the healthy subjects, the total body clearance of R(-)-tocainide was significantly greater than that of S(+)-tocainide (2.62 vs 1.70 ml.min-1.kg-1). Renal clearance also favoured R(-)-tocainide and appeared to contribute significantly to the stereoselective total body clearance. The volume of distribution of the enantiomers did not differ significantly. Uraemia produced a marked decrease in the total body clearance with no apparent effect on the volume of distribution of both enantiomers. The S/R ratio for total body clearance decreased significantly from 0.66 in healthy subjects to 0.54 in the uraemics, while the ratio for terminal elimination half-life significantly increased from 1.43 to 1.59. These results indicate that uraemia alters the degree of stereoselectivity in the pharmacokinetic parameters of tocainide enantiomers.

Biopsychosocial aspects of long-term survival on end-stage renal failure therapy.

At ten-years follow-up of 64 haemodialysis patients, 43 had died and 21 were alive, twelve with cadaver renal transplants and nine on haemodialysis. Examination of the influence of psychological, demographic, physical and biochemical factors revealed the Beck Depression Inventory and age as the two most important predictors of survival. The behaviour of the patient was directly responsible for five (11.6%) of the deaths, by suicide in three cases and dietary non-compliance in two cases. Hypothetical mechanisms linking depression with reduced survival have been reviewed. As the impact of depression on survival was maximal in the first few years of dialysis, monitoring for depression should be incorporated into routine care from the start of dialysis together with evaluative interventions that might enhance survival.

In vitro protein binding of propafenone in normal and uraemic human sera.

The protein binding of propafenone, a Class I antiarrhythmic agent, was studied in vitro using a selective and sensitive electron-capture detection gas-liquid capillary chromatographic assay method developed in our laboratory. The concentration-dependency of the serum protein binding of propafenone was confirmed in vitro by equilibrium dialysis, using serum obtained from healthy human subjects and patients with chronic renal failure. In normal serum the unbound fraction of propafenone was 0.027 at a propafenone concentration of 0.25 microgram.ml-1, 0.041 within the therapeutic concentration range (0.5-2 micrograms.ml-1), 0.138 at a propafenone concentration of 25 micrograms.ml-1, and 0.187 when the propafenone concentration was increased to 100 micrograms.ml-1. There was no evidence of significant concentration-dependent changes in unbound fraction within the propafenone concentration range of 0.5-1.5 micrograms.ml-1. However, concentration-dependent binding was demonstrated at concentrations greater than 1.5 micrograms.ml-1. A high-affinity, low-capacity binding site (K1 = 6.53 x 10(5) l.mol-1; n1P1 = 1.73 x 10(-4) mol.l-1) and a low-affinity, high-capacity binding site (K2 = 8.77 x 10(3) l.mol-1; n2P2 = 8.57 x 10(-3) mol. x l-1) were identified. In pooled uraemic serum the unbound fraction of propafenone was approximately 50% of that of normal serum throughout the concentration range studied (1-5 micrograms.ml-1). In sera from patients with chronic renal failure the increase in propafenone binding ratio or the decrease in unbound fraction was associated with the increase in alpha 1-acid glycoprotein concentrations, and there was a correlation (r = 0.8302) between alpha 1-acid glycoprotein concentration and the propafenone binding ratio.